In other studies which we have made, we have considered the effects of glucosinolates. Glucosinolates are naturally-occurring constituents of cruciferous vegetables (Tookey, H. L., VanEtten, C. H. and Daxenbichler, M. E. (1980) Glucosinolates. In Liener, I. E. (ed.), Toxic Constituents of Plant Foodstuffs. Second Edition, Academic Press, New York, Chapter 4, pp. 103-142). Sinigrin and glucobrassicin are two major glucosinolates found in cabbage, cauliflower, and brussels sprouts (Sones, K., Heaney, R. K. and Fenwick, G. R. (1984) An estimate of the mean daily intake of glucosinolates from cruciferous vegetables in the UK. J. Sci. Food Agric., 35, 712-720; VanEtten, C. H., Daxenbichler, M. E., Williams, P. H. and Kwolek, W. F. (1976) Glucosinolates and derived products in cruciferous vegetables. Analysis of the edible part from twenty-two varieties of cabbage. J. Agric. Food Chem., 24, 452-455). Indole-3-carbinol (I3C) is a major product of thioglucosidase-catalyzed hydrolysis of glucobrassicin (Loub, W. D., Wattenberg, L. W. and Davis, D. W. (1975) Aryl hydrocarbon hydroxylase induction in rat tissues by naturally occurring indoles of cruciferous plants. J. Natl. Cancer Inst., 54, 985-988; Bradfield, C. A. and Bjeldanes, L. F. (1987) High-performance liquid chromatographic analysis of anticarcinogenic indoles in Brassica oleracea. J. Agric. Food Chem., 35, 46-49). Glucosinolates and their derived isothiocyanates and indoles can modulate tumorigenesis. Glucobrassicin and glucotropaeolin, the precursor of benzyl isothiocyanate, decreased tumors induced by benzo[a]pyrene (BP) in ICR/Ha mouse lung, BP-induced pulmonary adenomas in A/J mice, and mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in Sprague-Dawley rats when each glucosinolate was administered orally prior to carcinogen dosing (Wattenberg, L. W., Hanley, A. B., Barany, G., Sparnins, V. L., Lam, L. K. T. and Fenwick, G. R. (1986) Inhibition of carcinogenesis by some minor dietary constituents. In Hayashi, Y., Nagao, M., Sugimura, T., Takayama, S., Tomatis, L., Wattenberg, L. W. and Wogan, G. N. (eds), Diet Nutrition and Cancer. Japan Sci. Soc. Press, London/VNU Sci. Press, Utrecht, pp. 193-203). I3C, a good inducer of aryl hydrocarbon hydroxylase and glutathione-S-transferase (Loub, W. D., Wattenberg, L. W. and Davis, D. W. (1975) Aryl hydrocarbon hydroxylase induction in rat tissues by naturally occurring indoles of cruciferous plants. J. Natl. Cancer Inst., 54, 985-988; Wattenberg, L. W., Loub, W. D., Lam, L. K. and Speier, J. L. (1976) Dietary constitutents altering the responses to chemical carcinogens. Fed. Proc., 35, 1327-1331; Sparnins, V. L., Venegas, P. L. and Wattenberg, L. W. (1982) Glutathione-S-transferase activity: enhancement by compounds inhibiting chemical carcinogenesis and by dietary constituents. J. Natl. Cancer Inst., 68, 493-496), has been found to inhibit BP-induced neoplasia in ICR/Ha forestomach, DMBA-induced mammary neoplasia in Sprague-Dawley rats and aflatoxin B.sub.1 -induced hepatic tumorigenicity in rainbow trout when administered by gavage or in the diet (Wattenberg, L. W.., and Loub, W. D. (1978) Inhibition of polycyclic aromatic hydrocarbon-induced neoplasia by naturally occurring indoles. Cancer Res., 38, 1410-1413; Nixon, J. E., Hendricks, J. D., Pawlowski, N. E., Pereira, C. B., Sinnhuber, R. O. and Bailey, G. S. (1984) Inhibition of aflatoxin B.sub.1 carcinogenesis in rainbow trout by flavone and indole compounds. Carcinogenesis, 5, 615-619).
The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is the most potent carcinogenic nitrosamine found in tobacco (Hecht, S. S., Trushin, N., Castonguay, A. and Rivenson, A. (1986) Comparative tumorigenicity and DNA methylation in F344 rats by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N-nitrosodimethylamine. Cancer Res., 46, 498-502). The ability of NNK to induce a high incidence of lung tumors at low doses regardless of the route of administration in all animal species tested (Hecht, S. S., Trushin, N., Castonguay, A. and Rivenson, A. (1986) Comparative tumorigenicity and DNA methylation in F344 rats by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N-nitrosodimethylamine. Cancer Res., 46, 498-502; International Agency for Research on Cancer (1985) Evaluation of the carcinogenic risk of chemicals to humans: tobacco habits other than smoking; Betel-Quid and Areca-nut chewing; and some related nitrosamines. IARC Monographs, 37, 209-224) suggests a possible role in the induction of lung cancer in smokers. When administered s.c. in rats, NNK also induces tumors of the liver and nasal cavity. While sinigrin inhibited NNK metabolism and its subsequent DNA methylation in liver, I3C enhanced hepatic metabolism of NNK (Chung, F.-L., Wang, M. and Hecht, S. S. (1985) Effects of dietary indoles and isothiocyanates on N-nitrosodimethylamine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone alpha-hydroxylation and DNA methylation in rat liver. Carcinogenesis, 6, 539-543). We have also examined in three NNK target tissues the effects of dietary sinigrin and I3C on two factors which may be important in NNK tumorigenesis: DNA methylation and O.sup.6 -methylguanine-DNA transmethylase activity. The results of these studies were compared with tumorigenicity data obtained from a two-year bioassay in which NNK-treated rats were fed control or sinigrin-containing diets.
We previously demonstrated that isothiocyanates, such as phenethyl isothiocyanate and phenyl isothiocyanate showed a wide range of inhibitory activities toward demethylation of nitrosamines, including NNK, in acute and chronic studies. Chronic, but not acute, pretreatment with sinigrin also caused a significant decrease in the demethylation of NDMA and NNK. The effects of phenethyl isothiocyanate, phenyl isothiocyanate, and sinigrin on the in vivo methylation of DNA by NDMA and NNK were also evaluated. (Chung, Fung-Lung; Wang, Minyao; Hecht, Stephen S. Chemical Abstracts 102:214760W(1985)). The results were parallel to those obtained in the in vitro assays. Phenethyl isothiocyanate, phenyl isothiocyanate, and sinigrin generally inhibited the formation of 7-methylguanine and O.sup.6 -methylguanine in rat hepatic DNA. The results of that study suggested that these compounds could be tested to determine if they were anticarcinogenic to NNK. The results did not suggest the remarkable inhibitory effects which we have now discovered are possessed by the compounds of the instant invention.